Kidney transplantation is the preferred treatment modality for patients with end-stage kidney disease. Compared to dialysis, transplantation leads to improved quality of life, longer patient survival, and considerable cost reductions. Progress in medical therapy has dramatically improved short-term survival of deceased donor kidney transplants (DDKT); however, long-term results remain poor with ten year graft survival rates of only 33.8% in African Americans (AAs), significantly shorter than the 45% survival in European Americans (EAs). New tools to improve long-term graft survival are urgently needed. Genetic risk variants in the Apo lipoprotein L1 (APOL1), multi-drug resistance 1 encoding P-glycoprotein (ABCB1), and caveolin-1 (CAV1) genes in kidney donors significantly shorten allograft survival, providing strong evidence that donor kidney gene variants impact transplant outcomes. This proposal would systematically search for genetic and environmental factors that impact graft survival after DDKT from AA donors. We propose to test variants in 58 replicated nephropathy susceptibility loci for association with long-term kidney transplant graft survival from AA donors. Interactive effects of gene variants with each other and with environmental stressors will be assessed. Human primary kidney cells containing the risk variants associated with allograft failure will then be assessed for alterations in gene expression profiles supporting the genetic association results. Analyses will be conducted in two phases: a discovery phase involving genetic data in 600 unrelated AA donor-kidney DNA samples (yielding 800-900 transplants) with validation in gene expression analyses and follow-up gene*gene and gene*environment interaction studies. A replication phase with an additional 200 AA DDKT DNA samples will be performed along with a combined analysis in all 800 AA kidney donors. Top donor gene associations will be assessed in kidney transplant recipient DNA samples to determine whether effects are specific to donor kidneys. These 58 nephropathy risk variants have improved our understanding of the pathogenesis of kidney disease; however, most have relatively weak effects and low predictive ability limiting clinical utility. We propose a systematic approach, analyzing nephropathy genes identified in genome-wide association studies in kidney transplantation where organs are stressed by prolonged lack of perfusion and exposure to nephrotoxic medications. These factors likely provide a suitable contrast to detect genetic contributors to renal graft survival. This work will likely improve outcomes after DDKT from donors of African ancestry and allow translation of genetic results in an important clinical realm.